Neurodevelopmental disorder therapy

ABSTRACT

This invention addresses tetrahydro-N, N-dimethyl-2,2diphenyl-3-furanmethanamine hydrochloride (ANAVEX2-73, AV2-73, or A2-73) in a method of treatment for neurodevelopmental disorders. Particular reference is made to the treatment of autism spectrum disorder, cerebral palsy, Rett syndrome, Angelman syndrome, Williams syndrome, pervasive developmental disorder not otherwise specified (PDD-NOS), childhood disintegrative disorder, and Smith-Magenis syndrome. Additional reference is made to multiple sclerosis.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/717,921 filed Dec. 17, 2019, which is a continuation of U.S. patentapplication Ser. No. 16/068,703 filed Jan. 15, 2019, which is a nationalstage filing under 35 U.S.C. § 371 of International Application No.PCT/US2017/014702, filed Jan. 24, 2017, which claims the benefit of U.S.Provisional Application No. 62/287,062 filed Jan. 26, 2016, thedisclosure of each of which is hereby incorporated by reference in itsentirety.

FIELD OF THE INVENTION

This invention addresses tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride (ANAVEX™ 2-73,AV2-73, or A2-73) in a method of treatment for neurodevelopmentaldisorders. Particular reference is made to the treatment of autismspectrum disorder, cerebral palsy, Rett syndrome, Angelman syndrome,Williams syndrome, pervasive developmental disorder not otherwisespecified (PDD-NOS), childhood disintegrative disorder, andSmith-Magenis syndrome. Additional reference is made to multiplesclerosis therapy.

BACKGROUND OF THE INVENTION

Neurodevelopmental disorders are generally categorized as disordersassociated with changes in early brain development. These typicallyexhibit themselves as behavioral and cognitive alterations in sensoryand motor systems, speech, and language. Particular reference is made toautism spectrum disorder, cerebral palsy, Rett syndrome, Angelmansyndrome, Williams syndrome, and Smith-Magenis syndrome.

Rett syndrome (RTT), originally termed cerebroatrophic hyperammonemia,is a rare genetic postnatal neurological disorder of the grey matter ofthe brain that almost exclusively affects females but has also beenfound in male patients. The clinical features include small hands andfeet and a deceleration of the rate of head growth (includingmicrocephaly in some). Repetitive stereotyped hand movements, such aswringing and/or repeatedly putting hands into the mouth, are also noted.People with Rett syndrome are prone to gastrointestinal disorders and upto 80% have seizures. They typically have no verbal skills, and about50% of affected individuals do not walk. Scoliosis, growth failure, andconstipation are very common and can be problematic.

The signs of this disorder are most easily confused with those ofAngelman syndrome, cerebral palsy, and autism. Rett syndrome occurs inapproximately 1:10,000 live female births in all geographies, and acrossall races and ethnicities.

Without being bound by any particular theory it is believed that Rettsyndrome is caused by mutations in the gene MECP2 located on the Xchromosome (which is involved in transcriptional silencing andepigenetic regulation of methylated DNA), and can arise sporadically orfrom germline mutations. Reportedly, in less than 10% of RTT cases,mutations in the genes CDKL5 or FOXG1 have also been found to resembleit. Rett syndrome is initially diagnosed by clinical observation, butthe diagnosis is definitive when there is a genetic defect in the MECP2gene.

Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride(ANAVEX2-73, AV2-73, or A2-73) is a compound which is believed to bindto muscarinic acetylcholine and sigma-1 receptors with affinities in thelow micromolar range. It has been reported that A2-73 showedneuroprotective potential against amyloid toxicity in mice. Inparticular, A2-73 has been reported as attenuating oxidative stress,caspases induction, cellular loss and learning and memory deficitsobserved in mice one week after the i.v. injection of an oligomericpreparation of amyloid β25-35 peptide (Aβ25-35) (Villard et al., J.Psychopharmacol. 2011). More recently, it has been reported that A2-73blocked the Aβ25-35-induced P-Akt decrease and P-GSK-3β increase,indicating activation of the PI3K neuroprotective pathway (Lahmy et al.,Neuropsychopharmacology, 2013). In the dose-range tested, A2-73attenuated the hyperphosphorylation of Tau on physiological epitopes(AT-8 antibody clone) and on pathological epitopes (AT-100 clone). A2-73also has been reported decreasing the Aβ25-35-induced endogenous Aβ1-42seeding.

It has been reported that neurodevelopmental disorders respond toN-methyl-D-aspartate receptor (NMDAR) antagonists and combinationtherapy. Reference is made to NMDAR antagonists selected from the groupconsisting of Amantadine, AZD6765, Dextrallorphan, Dextromethorphan,Dextrorphan, Diphenidine, Dizocilpine (MK-801), Ethanol, Eticyclidine,Gacyclidine, Ibogaine, Memantine, Methoxetamine, Nitrous oxide,Phencyclidine, Rolicyclidine, Tenocyclidine, Methoxydine, Tiletamine,Xenon, Neramexane, Eliprodil, Etoxadrol, Dexoxadrol, WMS-2539, NEFA,Delucemine, 8A-PDHQ, Aptiganel, HU-211, Remacemide, Rhynchophylline,Ketamine, 1-Aminocyclopropanecarboxylic acid (ACPC), 7-Chlorokynurenate′DCKA (5,7-dichlorokynurenic acid), Kynurenic acid, Lacosamide,L-phenylalanine, Neurotransmitters, Psychedelics, Long-termpotentiation, and NMDA.

Reference is made to the following publications. These publications, andall publications cited herein, are incorporated by reference in theirentirety:

-   -   1. “Rett Syndrome Fact Sheet. NIH Publication No. 09-4863”.        National Institute of Neurological Disorders and Stroke (NINDS).        November 2009.    -   2. Guy et al., (2007). “Reversal of Neurological Defects in a        Mouse Model of Rett Syndrome.” Science 315 (5815): 1143-7.        doi:10.1126/science.1138389. PMID 17289941.    -   3. Trappe et al, “MECP2 Mutations in Sporadic Cases of Rett        Syndrome Are Almost Exclusively of Paternal Origin.” The        American Journal of Human Genetics 68 (5): 1093-101.    -   4. Fitzgerald et al (1990). “Rett syndrome and associated        movement disorders”. Movement Disorders 5 (3): 195-202.    -   5. Ricceri et al (2008). “Mouse models of Rett syndrome: From        behavioural phenotyping to preclinical evaluation of new        therapeutic approaches”. Behavioural Pharmacology 19 (5-6):        501-17. doi:10.1097/FBP.0b013e32830c3645. PMID 18690105.    -   6. Lombardi, et al, “MECP2 disorders: from the clinic to mice        and back,” J Clin Invest. 2015 Aug. 3; 125(8):2914-23. doi:        10.1172/JCI78167. Epub 2015 Aug. 3. Review.    -   7. Pohodich et al, “Rett syndrome: disruption of epigenetic        control of postnatal neurological functions.” Hum Mol Genet.        2015 Oct. 15; 24 (R1): Epub 2015 Jun. 9.    -   8. Lotan et al, Rett Syndrome: Therapeutic Interventions        (Disability Studies) 1st Ed (Nova Science Publishers, Inc 2011)        PMID: 26060191.    -   9. U.S. Pat. No. 9,180,106 (Vamvakides) “Sigma receptors ligands        with anti-apoptotic and/or pro-apoptotic properties, over        cellular mechanisms, exhibiting prototypical cytoprotective and        also anti-cancer activity.”    -   10. Mallon et al, “EuroPhenome and EMPReSS: online mouse        phenotyping resource,” Nucleic Acids Res. 2008 January; 36        (Database issue): D715-8. Epub 2007 Sep. 28.    -   11. Morgan et al, “EuroPhenome: a repository for high-throughput        mouse phenotyping data,”. Nucleic Acids Res. 2010 January; 38        (Database issue): D577-85. doi: 10.1093/nar/gkp1007. Epub 2009        Nov. 23.    -   12. Tropea et al., “Partial reversal of Rett Syndrome-like        symptoms in MeCP2 mutant mice”. Proceedings of the National        Academy of Sciences 106 (6): 2029-34. (2009),    -   13. Tan et al., “Pharmacological therapies for Angelman        syndrome,” Wien Med Wochenschr. 2016 Jan. 12. [Epub ahead of        print]    -   14. US Pub. No 2015/0152410 to Kreig et al., entitled        “Compositions And Methods For Modulating Mecp2 Expression.”    -   15. US Pub. No 2015/0265554 to Roux et al, “Treatment of MeCP-2        Associated Disorders.”    -   16. U.S. Pat. No. 7,994,127 to Sur et al., Treatment of Rett        Syndrome And Other Disorders.

SUMMARY OF THE INVENTION

The claimed invention concerns a method of treating a neurodevelopmentaldisorders such as Rett syndrome in a subject by administering to saidsubject a therapeutically effective amount of A2-73. In particularembodiments this includes a dosage form comprising a therapeutic amountof A2-73. Note is made of the dosages of A2-73 from about 0.5 to about500 mg. This invention further includes a therapeutic method of treatingneurodevelopmental disorders such as autism spectrum disorder, cerebralpalsy, Rett syndrome, Angelman syndrome, Williams syndrome, andSmith-Magenis syndrome. Additional mention is made of multiple sclerosistherapy using A2-73.

Therapeutic doses of A2-73 are particularly noted in a range of fromabout 0.5 mg/day to about 100 mg/day with particular reference to dosesof from about 1 to about 60 mg/day and, optionally, wherein said dosageis administered daily for at least about 10 days. Adult doses of about20 mg to about 50 mg/day are noted, with particular reference to about30 mg to about 40 mg/day. Infant and child doses are to the lower end ofthe range with particular reference to from about 0.5 mg/day to about 20mg/day. Chronic administration for chronic conditions is furthercontemplated. Further contemplate is the therapeutic use of A2-73analogues tetrahydro-N,N-dimethyl-5,5-diphenyl-3-furanmethanaminehydrochloride (ANAVEX™ 1-41), and1-(2,2-diphenyltetrahydrofuran-3-yl)-N-methylmethanamine hydrochloride(ANAVEX™ 19-144, or A19-144). These A2-73 analogues are contemplated foruse at dosages and dosage ranges similar to A2-73.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphic presentation of body weight of vehicle-treated andwild-type and mutant control mice.

FIGS. 2A and 2B are graphic representations of rotarod stability testsof vehicle-treated 8 week old mutant mice compared to vehicle-treated WTmice.

FIGS. 3A and 3B are graphic representations of rotarod stability testsof vehicle-treated 12 week old mutant mice compared to vehicle-treatedWT mice.

FIGS. 4A and 4B are pictures of mice showing unclasped and clasped hindleg responses.

FIG. 5 is a graphic presentation of clasping responses in mutant andwildtype mice treated with A2-73.

FIGS. 6A and 6B are graphic results of pre pulse inhibition (PPI) instartle response tests in mutant and wildtype 8 week old mice treatedwith A2-73.

FIGS. 7A and &B are graphic results of pre pulse inhibition (PPI) instartle response tests in mutant and wildtype 12 week old mice treatedwith A2-73.

FIGS. 8A-C show Neurocube data (8 week old mice).

FIG. 9A-D graphically display gait differences which appeared to berescued while others enhanced the mutant gait phenotype.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “therapeutically effective amount” of an agent orcombination of agents is an amount sufficient to achieve a desiredtherapeutic or pharmacological effect. Particular reference is made toan amount that is capable of ameliorating biochemical and functionalabnormalities associated with loss-of-function mutations of the geneencoding methyl-CpG binding protein 2 (MeCP2). It is to be understoodthat a therapeutically effective amount of an agent or combinatorytherapy may vary according to factors such as the disease state, age,and weight of the subject, and the ability of the agent to elicit adesired response in the subject. Dosage regimens may be adjusted toprovide the optimum therapeutic response. A therapeutically effectiveamount is also one in which any toxic or detrimental effects of theactive compound are outweighed by the therapeutically beneficialeffects.

Studies employed wild type (WT) mice and heterozygous MECP2 knockoutmice (HET) All mice were provided by Jackson Laboratory, Bar Harbor, Me.HET mice were Bird mice (Jackson Laboratories, Bar Harbor, Me.,B6.129P2(C)-Mecp2^(tm1.1Bird)/Stock Number: 003890) were obtained bycrossing het females with wild type (WT) males (C57B/6J).129P2(C)-Mecp2^(tm1.1Bird)/J is a constitutive Mecp2 knockout thatexhibits Rett syndrome-like neurological defects.

Breeding of the test mice done at Jackson Laboratories (FarmingtonConnecticut). Mice were shipped at 4-5 weeks of age.

Mecp2 females testing at ˜8 and ˜12 weeks of age

20 WT—vehicle (0.25% MC/dH2O)

20 HET—vehicle (0.25% MC/dH2O)

20 HET—A2-733 (10 mg/kg)

20 HET—A2-733 (30 mg/kg)

Chronic dosing (p.o.) daily, starting at ˜5.5 weeks of age andcontinuing through the 12-week behavioral testing time point 60 minpre-treatment during behavioral testing.

Body Weight

No differences were observed in body weight between vehicle-treatedwild-type and mutant control mice. FIG. 1 There was a significantTreatment×Age effect (p<0.001), where mice treated with A2-733 (30mg/kg) weighed less than vehicle-treated mutant mice 6.5 weeks afterdosing began.

Rotarod

The rotarod performance test is a performance test based on a rotatingrod with forced motor activity being applied, usually by a rodent. Thetest measures parameters such as riding time (seconds) or endurance.Some of the functions of the test include evaluating balance, gripstrength, and motor coordination of the subjects; especially in testingthe effect of experimental drugs or after traumatic brain injury.

Mice are placed on the rotarod apparatus (PsychoGenics, Tarrytown N.Y.)consisting of a rod that rotates at a constant or variable andaccelerating speed of 4 rpm. Once a mouse loses its balance and fallsonto an underlying platform the timer automatically stops. Mice areexposed to the apparatus for 5 min training at a constant speed andplaced back on the rod after each fall. After a rest period of at least1 hr. animals are placed back on the rotarod apparatus for testing. Onceall animals in a test session are loaded on the rod, the rotarodapparatus is placed on accelerating speed (0-40 rpm) over 5 min and thetime until the first fall is recorded. The test is repeated threeconsecutive times per animal. For each test session, the RPM score attime of fall off the rod are recorded.

Rotarod at 8 Weeks [FIG. 2A and FIG. 2B]

Vehicle-treated mutant mice fell more rapidly and at lower speedscompared to vehicle-treated WT mice. No significant treatment effectswere observed for either measure.

Rotarod at 12 Weeks [FIG. 3A and FIG. 3B]

Vehicle-treated mutant mice fell more rapidly and at lower speedscompared to vehicle-treated WT mice. A2-733-treated mice at both dosestook more time to fall off the rod and fell at higher speeds compared tovehicle-treated mutant mice. Without outliers, the effect at the higherdose disappeared for the speed at fall measure. Mutant mice were slowerand fell more quickly at both 8 and 12 weeks of age compared to wildtypecontrols.

Clasping [FIG. 4A and FIG. 4B]

Mice are lifted gently by the tail with front limbs remaining onsurface. Clasping of hind legs is noted (normal is a spread in the hindlegs).

Clasping at 8 Weeks [FIG. 5]

Vehicle-treated mutant mice clasped more than vehicle-treated wild typemice. Mice treated with A2-733 (30 mg/kg) clasped less thanvehicle-treated mutant mice.

Startle/PPI

The acoustic startle measures an unconditioned reflex response toexternal auditory stimulation. Mice are placed in the prepulseinhibition (PPI) chambers for a 5 min session of white noise (70 dB)habituation. Then the session starts with a habituation block of 6presentations of the startle stimulus alone, followed by 10 PPI blocksof 6 different types of trials [null (no stimuli), startle (120 dB),startle plus prepulse (4, 8 and 12 dB over background noise i.e. 74, 78or 82 dB) and prepulse alone (82 dB)] presented at random within eachblock. The amount of inhibition of the normal startle is determined andexpressed as a percentage of the basic startle response (from startlealone trials), excluding the startle response of the first habituationblock.

Startle/PPI 8 Weeks [FIG. 6A and FIG. 6B]

Vehicle-treated mutant mice startled less and but showed no differencesin PPI response compared to vehicle-treated WT mice. A2-733 (30 mg/kg)treated mice showed an increased startle response compared tovehicle-treated mutant mice. No treatment differences were observed inPPI.

Startle/PPI 12 Weeks [FIG. 7A and FIG. 7B]

Vehicle-treated mutant mice startled less but showed no differences inPPI response compared to vehicle-treated WT mice. There was a trend of atreatment effect in the startle response (p<0.08). With outliersremoved, this trend became significant, with A2-733 (30 mg/kg) miceshowing increased startle compared to vehicle-treated mutant mice(p<0.01). The PPI treatment interaction (p<0.05) did not reveal anysignificant post hoc differences.

Neurological testing via a platform that employs computer vision todetect changes in gait geometry and gait dynamics in rodent models ofneurological disorders, pain, and neuropathies. Complex bio-informaticsalgorithms similar to those used in SmartCube® are employed to detect adisease phenotype and screen compounds. (NeuroCube, PsychoGenics,Tarrytown N.Y.)

A platform that employs computer vision to detect changes in gaitgeometry and gait dynamics in rodent models of neurological disorders,pain, and neuropathies. Mice are allowed to walk in the chamber for 5min. When the paw touches the screen, LED light reflects creating brightspots. Images are captured and processed using proprietary computervision and bio-informatics data mining algorithms.

FIGS. 8A-C graphically display Neurocube 8 week data. Significantseparation between WT and HET vehicle mice (p=0). There was noseparation between A2-733 versus Het vehicle. There was 9-17% recoveryof the overall signature due to mild beneficial effects of the drug ongait and imaging features.

FIGS. 9A-D graphically display gait differences which appeared to berescued while others enhanced the mutant gait phenotype.

NeuroCube 8 week gait analysis is presented in Table 1 (below):

Het vehicle v. Het vehicle v. WT vehicle v. Het AV2-73, Het AV2-73, Hetvehicle 10 mg/kg 30 mg/kg Overall 90, p = 0   53, p > 0.69 62, p > 0.24GAIT 78, p < 0.01 63, p > 0.09 69, p < 0.05 Paw Features  91, p < 0.00152, p > 0.78 55, p > 0.56 Correlation 53, p > 0.66 56, p > 0.40  76, p <0.005 Body Motion 71, p < 0.02 60, p > 0.20  81, p < 0.003 PawPositioning  84, p < 0.0001 53, p > 0.57 57, p > 0.36

NeuroCube 12 week gait analysis is presented in Table 2 (below):

Het vehicle v. Het vehicle v. WT vehicle v. Het AV2-73, Het AV2-73, Hetvehicle 10 mg/kg 30 mg/kg Overall 95, p = 0 53, p > 0.70 61, p > 0.21GAIT    77, p < 0.0001 57, p > 0.29 57, p > 0.37 Paw Features 86, p = 056, p > 0.35 53, p > 0.65 Correlation    76, p < 0.005 53, p > 0.70 69,p < 0.03 Body Motion 83, p = 0 52, p > 0.71 68, p < 0.04 Paw Positioning   80, p < 0.001 53, p > 0.57 53, p > 0.62

It is believed that therapeutic doses of A-2-73 increases lifespan andimproves locomotor, respiratory, and cardiac function in children withRett Syndrome.

EXAMPLE 1 Breathing Variability Reduction

A 6 year old female presenting with Rett syndrome is administered oraldoses of A2-73 at 4 mg daily for 10 days. On presentation, her breathingis abnormal. Her mean breaths per minute is calculated to assessbreathing variability. After 10 days of A2-73, administration the 0(breaths/minute) was significantly reduced (implying less variability).

EXAMPLE 2 Cardiac Pulse Rate

A 10 year old female presents with Rett syndrome. Her real time cardiacpulse rate is monitored. Prior to commencing therapy, her heart rate is49 beats per minute with substantial variability. Following treatmentwith oral doses of A2-73 at 20 mg daily for 5 days, the variability isreduced while the average rate is increased to 75 beats per minutes.

EXAMPLE 3 Seizure Reduction

An 18 month old female presents with Rett syndrome. She experiences 6 to10 seizures per day prior to commencing therapy. She begins treatmentwith oral doses of A2-73 at 2 mg daily. After 5 days of treatment, thenumber of daily seizures is reduced to 3 or fewer.

EXAMPLE 4 Eating and Choking

A 20 year-old female presents with Rett syndrome. She experiencesfeeding difficulties exhibiting as choking and poor food intake prior tocommencing therapy. She begins treatment with oral doses of A2-73 at 40mg every other day. After 60 days of treatment, the instances of chokingare reduced and she exhibits a 10% weight gain.

EXAMPLE 5 Angelman—Sleep and Seizures

A 25 year-old male presents with Angelman syndrome. He experiencesdisturbed sleep and frequent seizures prior to commencing therapy. Hebegins treatment with oral doses of A2-73 at 30 mg/day. After 15 days oftreatment, his sleep is markedly less disturbed and his instances ofseizure are reduced by 50%.

EXAMPLE 6 Williams Syndrome—Weight Gain

A 2 year-old male presents with Williams syndrome. He exhibits a failureto thrive with low weight gain. He begins treatment with i.v. doses ofA2-73 at 5 mg every other day. After 60 days of treatment, he exhibits a10% weight gain.

EXAMPLE 7 Smith-Magenis Syndrome—Sleep

A 5 year-old male presents with Smith-Magenis syndrome. He experiencesdisturbed sleep. He begins treatment with oral doses of A2-73 at 10mg/day. After 15 days of treatment, his sleep is markedly lessdisturbed.

EXAMPLE 8 Multiple Sclerosis

A 17 year-old male presents with multiple sclerosis. He begins treatmentwith oral doses of A2-73 at 40 mg every fifth day. The total number ofgadolinium-enhanced lesions on MRI at weeks 12, 16, 20 and 24 issubstantially reduced as compared to his 12 week pretreatment MRI.

EXAMPLE 9 Multiple Sclerosis

A 27 year-old female presents with relapsing-remitting multiplesclerosis. She begins treatment with oral doses of A2-73 at 30 mg everyother day for 3 months. She exhibits a significantly lower number oftotal gadolinium-enhancing lesions on monthly brain MRI up to month 6.

The pharmaceutical compositions provided herein can be administeredchronically (“chronic administration”). Chronic administration refers toadministration of a compound or pharmaceutical composition thereof overan extended period of time, e.g., for example, over 3 months, 6 months,1 year, 2 years, 3 years, 5 years, etc., or may be continuedindefinitely, for example, for the rest of the subject's life. Incertain embodiments, the chronic administration is intended to provide aconstant level of the compound in the blood, e.g., within thetherapeutic window over the extended period of time.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the compound is usually aminor component (from about 0.1 to about 50% by weight or preferablyfrom about 1 to about 40% by weight) with the remainder being variousvehicles or carriers and processing aids helpful for forming the desireddosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as a ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor Formulation. All such known transdermal formulations and ingredientsare included within the scope provided herein.

The compounds provided herein can also, in some embodiments, beadministered by a transdermal device. Accordingly, transdermaladministration can be accomplished using a patch either of the reservoiror porous membrane type, or of a solid matrix variety.

The noted components for orally administrable, injectable or topicallyadministrable compositions are merely representative. Other materials aswell as processing techniques and the like are set forth in Remington:The Science and Practice of Pharmacy, 22^(nd) Edition (2012),Pharmaceutical Press, which is incorporated herein by reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

What is claimed is:
 1. A method of ameliorating biochemical andfunctional abnormalities associated with methyl-CpG binding protein 2defects (MeCP2 defects) in a subject by administering to the subject inneed thereof a composition comprising a therapeutically effective amountof a therapeutic agent selected from the group of Anavex2-73, an analogof Anavex2-73, and a combination thereof.
 2. The method of claim 1,wherein the biochemical and functional abnormalities associated withMeCP2 defects manifest as neurodevelopmental or neurological diseases.3. The method of claim 2, wherein the neurodevelopmental or neurologicaldiseases comprises multiple sclerosis, Rett Syndrome, cerebral palsy,Angelman syndrome, Williams syndrome, pervasive developmental disordernot otherwise specified (PDD-NOS), childhood disintegrative disorder,Smith-Magenis syndrome, non-syndromic mental retardation, idiopathicneonatal encephalopathy, idiopathic cerebral palsy, or autism spectrumdisorder.
 4. The method of claim 1, wherein the biochemical andfunctional abnormalities associated with MeCP2 defects comprisesabnormal breathing, abnormal cardiac function, abnormal feeding orchoking, weight gain failure, abnormal sleep or seizure.
 5. The methodof claim 1, wherein the therapeutic agent is Anavex2-73.
 6. The methodof claim 1, wherein the therapeutic agent is the analog of Anavex2-73selected from the group consisting of A1-41, A19-144, and a combinationthereof.
 7. The method of claim 1, wherein the therapeutically effectiveamount is a dosage from about 0.5 mg/day to about 100 mg/day.
 8. Themethod of claim 1, wherein the composition is selected from a groupconsisting of an oral composition, a transdermal composition and aparenteral composition.
 9. The method of claim 1, wherein the subject isan adult, a child, or an infant.
 10. The method of claim 1, wherein thesubject is a child or an infant and the dosage ranges from about 0.5mg/day to about 20 mg/day.
 11. A method of treating disorders associatedwith methyl-CpG binding protein 2 defects (MeCP2 defects) in a subjectby administering to the subject in need thereof a composition comprisinga therapeutically effective amount of a therapeutic agent selected fromthe group of Anavex2-73, an analog of Anavex2-73, and a combinationthereof.
 12. The method of claim 11, wherein the disorders associatedwith MeCP2 defects comprises a neurodevelopmental or a neurologicaldisease.
 13. The method of claim 12, wherein the neurodevelopmental orneurological disease comprises multiple sclerosis, Rett Syndrome,cerebral palsy, Angelman syndrome, Williams syndrome, pervasivedevelopmental disorder not otherwise specified (PDD-NOS), childhooddisintegrative disorder, Smith-Magenis syndrome, non-syndromic mentalretardation, idiopathic neonatal encephalopathy, idiopathic cerebralpalsy, or autism spectrum disorder.
 14. The method of claim 13, whereinthe neurodevelopmental or neurological diseases is treated bynormalizing breathing, normalizing cardiac function, normalizing feedingand avoiding choking, obtaining weight gain, normalizing sleep orreducing seizure.
 15. The method of claim 11, wherein the therapeuticagent is Anavex2-73.
 16. The method of claim 11, wherein the therapeuticagent is the analog of Anavex2-73 selected from the group consisting ofA1-41, A19-144, and a combination thereof.
 17. The method of claim 11,wherein the therapeutically effective amount is a dosage from about 0.5mg/day to about 100 mg/day.
 18. The method of claim 11, wherein thecomposition is selected from a group consisting of an oral composition,a transdermal composition and a parenteral composition.
 19. The methodof claim 11, wherein the subject is an adult, a child, or an infant. 20.The method of claim 11, wherein the subject is a child or an infant andthe dosage ranges from about 0.5 mg/day to about 20 mg/day.